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What is Pain?

What is Pain?. “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” International Association for the Study of Pain. Pain and temperature sensed by free nerve endings.

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What is Pain?

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  1. What is Pain? • “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” • International Association for the Study of Pain

  2. Pain and temperature sensed by free nerve endings

  3. Fiber diameter profile of peripheral nerves

  4. Heat and cold stimulate pain receptors (nociceptors)

  5. Temperature Sense • Normal skin temperature: T = 30-32 °C • Thermal sensations span four ranges: 1. Cold (T < 15 °C) 2. Cool (T > 15 °C and < 30 °C) 3. Warm (T > 35 °C and < 45 °C) 4. Hot (T > 45 °C) • Specific temperature-sensitive receptors code each range

  6. Thermal Receptors • Cold Receptors (TRPM8) • A-d fibers (thinly myelinated) • Stimulus: Cooling between T = 8 °C and 40 °C • Most sensitive at T = 25 °C • Saturate at T < 8 °C • Warm Receptors (TRPV3) • C fibers (unmyelinated) • Stimulus: Warming between T = 35 °C and 45 °C • Most sensitive at T = ~42 °C • Saturate at T > 45 °C

  7. Cold fibers signal rapid skin cooling

  8. Dynamic Response to Temperature

  9. Warm Receptors Code T > 35 °C

  10. Warm Receptors Saturate at High T

  11. Thermo-TRPs respond to specific temperature ranges TRP = Transient receptor potential

  12. Heat Nociceptors … and Burning Pain • A-d fibers (NS) or C fibers (HPC) • Express TRPV1 and/or TRPV2 receptors • Firing rate signals heat intensity at T > 45 °C • Response outlasts heat stimulus • Sensitize to repeated heat stimuli

  13. Noxious Cold (T < 10 °C) • Cold Fibers (TRPM8) • A-d fibers (thinly myelinated) • Saturate at T < 8 °C • Polymodal Nociceptors (HeatPinchCold) • C fibers (unmyelinated) • Firing rate signals degree of cooling at T < 25 °C • Fire at highest rates at T < 0 °C • Express TRPA1, TRPV1 and TRPM8 receptors • Paradoxical Cold: Freezing temperatures are perceived as burning pain

  14. Heat and cold stimulate specific groups of receptors

  15. What is Pain? • Aversive sensation • Intensity ranges from unpleasant to horrible • Various classes of pain • pricking, stabbing, pinching (mechanical ) • burning, freezing (thermal ) • aching, stinging, soreness (chemical ) • visceral (mechanical, chemical ) • Emotional component (pain tolerance) • Protective function • Warn of injury that should be avoided or treated

  16. Four classes of noxious (painful) sensations Heat pain Chemical Mechanical Cold pain

  17. Mechanical Nociceptors • Receptors specialized for painful mechanical stimuli (NociceptiveSpecific) • A-d fibers (thinly myelinated) • Do not respond to light touch (high threshold) • Excited by strong pressure, pinch or squeezing • Mediate pain from skeletal muscle or viscera due to excessive stretch or contractile force • Most respond to noxious heat (T > 45 °C)

  18. Mechanical nociceptors respond to prick and pinch

  19. Polymodal nociceptors • C fibers (unmyelinated free nerve endings) • Respond to heat, pinch and cold (HPC receptors) • Express TRPV1, TRPA1 and other TRP receptors • Respond to irritant chemicals • Capsaicin (chili peppers): TRPV1 receptors • Mustard oil, garlic, horseradish: TRPA1 receptor • Low pH (acids) • Endogenous peptides: Bradykinin, NGF • Environmental irritants and pollutants

  20. Polymodal nociceptors express multiple receptors

  21. Nociceptors Respond to Chemicals • Exogenous chemicals that penetrate skin • Acids, alkalis, organic molecules • Capsaicin, Mustard oil • Intracellular molecules released by cell injury • Cations [K+, H+] • Peptides, neurotransmitters • Prostaglandins, histamine • Toxins [micro-organisms, insect bites, venom] • Pathological substances released by diseased tissue

  22. Tissue Damage Stimulates Nociceptors

  23. TRP receptors respond to pungent chemicals Garlic, radishes, mustard oil Menthol Camphor Capsaicin

  24. Irritant chemicals activate TRP receptors

  25. Inflammation sensitizes nociceptors

  26. Noxious stimuli are spread by axon reflexes

  27. Hyperalgesia

  28. Touch and pain fibers project to distinct spinal laminae

  29. Pain Inputs to Spinal Cord

  30. Lamina I Cells Respond Only to Pain • Mechanical and Heat (NS) • Cold • Polymodal (Heat, Pinch, Cold) • Irritant Chemicals (Histamine, Capsaicin, Mustard Oil)

  31. Small Fiber Inputs to Spinal Cord

  32. Touch and pain fibers project to distinct spinal laminae

  33. Referred Pain: Wide Dynamic Range Neurons

  34. Touch and Pain Ascend in Separate Tracts

  35. Visceral pain transmitted in the dorsal columns T10 Central gray matter Willis WD, et al. PNAS 96: 7675-7679, 1999

  36. Pain Pathways to Thalamus and Cortex II

  37. Parallel Processing of Pain in Cortex • VPL/VPM —> SI Cortex • Pain localization to particular body site • VMpo —> Dorsal Insular Cortex • Pain sensation experienced (cold, heat, stab) • MDvc —> Anterior Cingulate Cortex • Pain emotional reaction • Hypothalamus and Limbic Cortex • Body physical response to pain • Subjective memory of pain

  38. Pain Centers in the Brain Apkarian et al. Eur J Pain 9: 463-484, 2005

  39. How Can We Reduce Pain? • Remove the painful stimulus • Flexion reflex (hard-wired circuit to avoid pain) • Treat injury or pathology • Analgesics and/or antihistamines • Block impulse conduction in peripheral nerve • Local anesthetics, epidural anesthesia • Block synaptic transmission in CNS • General anesthesia • Narcotic analgesics (e.g. morphine) • Activate body’s own pain control system

  40. Gate Control of Pain

  41. Emotions Modulate Pain Transmission (nucleus cuneiformis) (periaqueductal gray) (dorsolateral pontine tegmentum)

  42. Endogenous Pain Inhibition

  43. Endogenous Opioid Peptides • Leucine-enkephalin • Tyr-Gly-Gly-Phe-Leu-OH • Methionine-enkephalin • Tyr-Gly-Gly-Phe-Met-OH • b-endorphin • Tyr-Gly-Gly-Phe-[26 amino acids]-OH • Dynorphin • Tyr-Gly-Gly-Phe-[13 amino acids]-OH

  44. Opiates & Opioids Modulate Pain

  45. Pain Prevention • Local anesthetics as supplements or alternatives to general anesthesia • Intrathecal morphine intraoperatively • Postoperative pain relief • Physical therapy to stimulate large fibers • Psychotherapy to optimize use of descending pain control pathways and improve pain tolerance

  46. Pain Perception Involves Multiple Processes

  47. Nociceptive Pain: Somatosensory response

  48. Inflammatory pain: trauma or disease

  49. Two Classes of Pain • Nociceptive or Inflammatory Pain (Acute) • Sensation transmitted by free nerve endings • Stimulus provided by noxious (harmful) mechanical, thermal or chemical input • Protective function • Neuropathic Pain (Chronic) • Abnormal firing pattern in PNS or CNS • Caused by lesion or trauma to nerve or CNS • Sensitization of central pathways due to excessive painful input

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